Implantable devices for chemonucleolysis of intervertebral discs

ABSTRACT

Devices for the treatment of intervertebral discs are described. The devices, when implanted into the nucleus pulposus of an intervertebral disc, provide for the controlled release of active agents into the disc. The active agent can be a chemonucleolytic agent such as chymopapain. The device can also comprise one or more binders. The device can be an elongate solid body having a tapered or rounded insertion end. Alternatively, the device can include a plurality of particles.

CROSS-REFERENCE TO RELATED APPLICATIONS

The present application is a Divisional Application of U.S. applicationSer. No. 10/634,798 entitled “Methods And Devices For The Treatment OfIntervertebral Discs” filed on Aug. 06, 2003, incorporated herein byreference in its entirety.

BACKGROUND

1. Technical Field

The present application relates generally to methods and devices for thetreatment of intervertebral discs and, in particular, to controlledrelease devices comprising a chemonucleolysis agent or multiple activeagents and to methods of treatment comprising implanting the devicesinto an intervertebral disc.

2. Background of Technology

The intervertebral discs are cartilaginous plates surrounded by afibrous ring that lie between the vertebral bodies and serve to cushionthem. Through degeneration, wear and tear, and trauma, the fibroustissue (annulus fibrosus) constraining the soft disc material (nucleuspulposus) may tear or become compressed. This squeezing or protrusion ofthe disc has been called herniated disc ruptured disc, herniated nucleuspulposus, or prolapsed disc. The extruded nucleus pulposus may press ona spinal nerve which may result in nerve damage, pain, numbness, muscleweakness and even paralysis.

Common methods of providing relief for damaged intervertebral discsinclude surgical removal of all or a portion of the intervertebral discfollowed by fusion of the adjacent vertebrae. Although fusion caneliminate certain of the aforementioned symptoms, the restricted motionof the fused segment increases the range of motion required of theadjoining intervertebral discs and can therefore enhance theirdegeneration. As an alternative to fusion, the disc can be replaced witha spacer designed to simulate healthy intervertebral disc motion. Thematerials from which these disc spacers are made (e.g., polymeric andmetallic materials), however, may disintegrate in the body or break downunder repeated stress over prolonged periods.

Accordingly, there still exists a need for improved devices and methodsfor the treatment of intervertebral discs.

SUMMARY OF THE INVENTION

An intervertebral disc implant comprising a chemonucleolysis agent insolid form is provided wherein the chemonucleolysis agent is capable ofthe proteolytic degradation of the nucleus pulposus of an intervertebraldisc. The implant can be a solid body comprising the chemonucleolysisagent. The solid body can be an elongate solid body or a microsphere.The solid body can further comprise a binder. The binder can be abioresorbable polymer. Alternatively, the implant can comprise aplurality of unconsolidated particles at least some of which comprisethe chemonucleolysis agent. Exemplary chemonucleolysis agents includechymopapain or chondroitinase ABC.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 illustrates two alternative methods of preparing anintervertebral disc implant.

FIG. 2 illustrates a method of implanting an intervertebral disc implantas set forth in FIG. 1.

FIG. 3 illustrates the performance of an intervertebral disc implant asset forth in FIG. 1 after implantation into an intervertebral discspace.

FIG. 4 shows an intervertebral disc implant for the delivery of multiple(i.e., two) active agents.

FIG. 5 illustrates the performance of an intervertebral disc implant asset forth in FIG. 2 after implantation into an intervertebral discspace.

FIG. 6 illustrates a method of treating an intervertebral disc using anintervertebral disc implant as set forth in FIG. 2 wherein cells areinjected into the disc space after chemonucleolysis is complete.

FIG. 7 illustrates an intervertebral disc implant for the delivery ofmultiple (i.e., three) active agents.

FIG. 8 shows a microsphere comprising a chemonucleolysis agent.

FIG. 9 illustrates a method of treating an intervertebral disc whereinmicrospheres comprising a chemonucleolysis agent as shown in FIG. 8 aremixed in liquid solution and injected into an intervertebral disc space.

FIG. 10 illustrates an alternative embodiment of an intervertebral discimplant for the delivery of multiple (i.e., two) active agents.

FIG. 11 illustrates an alternative embodiment of an intervertebral discimplant for the delivery of multiple (i.e., three) active agents.

FIG. 12 illustrates an alternative embodiment of an intervertebral discimplant for the delivery of multiple (i.e., three) active agents havinga sheath/core configuration wherein two of the active agents are indifferent portions of the sheath and the third active agent is in thecore.

FIG. 13 illustrates an alternative embodiment of an intervertebral discimplant for the delivery of multiple (i.e., three) active agents havinga sheath/core configuration wherein one of the active agents is in thesheath and the second and third active agents are in different portionsof the core.

FIG. 14 illustrates an alternative embodiment of an intervertebral discimplant for the delivery of multiple (i.e., two) active agents having arod configuration wherein alternating portions of the rod contain eachof the two active agents.

FIG. 15 illustrates an alternative embodiment of an intervertebral discimplant for the delivery of multiple active agents having a rodconfiguration wherein segments of the rod contain different activeagents.

FIGS. 16A-16O illustrate various profile shapes for intervertebral discimplants.

FIG. 17 illustrates an alternative embodiment of an intervertebral discimplant for the delivery of multiple (i.e., two) active agents having arod configuration, a pointed insertion end and a hydrogel coating toprovide lubricity.

FIG. 18 illustrates an alternative embodiment of an intervertebral discimplant for the delivery of multiple (i.e., two) active agents having arod configuration, a pointed insertion end, a hydrogel coating toprovide lubricity and x-ray marker beads.

FIG. 19 illustrates an alternative embodiment of an intervertebral discimplant for the delivery of multiple (i.e., two) active agents having arod configuration, a pointed insertion end, a hydrogel coating toprovide lubricity and an x-ray marker thread.

FIGS. 20A and 20B illustrate a method of implanting an intervertebraldisc implant as shown in FIGS. 20A-200.

FIGS. 21A-21C are pictures of pig discs wherein FIG. 21A is a picture ofan untreated control disc, FIG. 21B is a picture of a disc treated withchymopapain in saline solution, and FIG. 21C is a picture of disctreated with an implant according to one embodiment of the inventioncomprising chymopapain and collagen powder.

DETAILED DESCRIPTION

Methods and devices for the localized delivery of active agents to anessentially intact intervertebral disc are provided. The disclosedmethods of treatment do not require the surgical removal of disctissues. The disclosed methods and devices can be used to treat variousconditions of the intervertebral disc including, but not limited to,protrusion, herniation, discogenic pain, dehydration and degeneration.The implants incorporate one or more active agents. By using theimplants, detrimental side effects typically associated with directinjection of an active agent in liquid form (including leakage andoverdose) can be reduced or eliminated. Methods of incorporating one ormore active agents into a compact implantable device are also provided.

The devices can be delivered into the nucleus pulposus through a smallopening or aperture in the annulus fibrosus. Once implanted, the devicecan provide a controlled and/or sustained release of one or more activeagents from the implanted device to the surrounding disc tissues.

According to one embodiment, the device can comprise an active agent anda inert binder or matrix material. The binder is preferably an inertmaterial. The binder can be chosen to provide an implant with desiredrelease characteristics.

The device can be of any size and shape suitable for implantation intothe inetrvertebral disc space of a mammal. Preferably, the device iscompact in cross-section for delivery to the disc space though a smallopening or aperture. According to one embodiment of the invention, thedevice is an elongate solid body. The elongate solid body can, forexample, be a rod having a rounded or tapered insertion end.

The proposed methods and devices offer several advantages and can beused for various treatments of the intervertebral disc. Exemplarytreatments include, but are not limited to, chemonucleolysis,pain-management, disc repair, and disc regeneration.

FIG. 1A illustrates two alternative methods of preparing anintervertebral disc implant. In a first method, an active agent 10(e.g., a chemonucleolysis agent such as chymopapain) is mixed 14 with abinder 12 in an appropriate ratio. When the active agent 10 ischymopapain, the chymopapain in powder form can be mixed with thebinder. The binder 12 can be a hygroscopic bioresorbable polymer. Theactive agent/binder mixture can then be consolidated under pressureand/or heat 16 into elongated rods 18. According to a preferredembodiment, the elongated rods can have a circular cross-section with adiameter of approximately 1 mm. Rods having a larger or smaller diametercan also be used.

In a second method of making an implant which is illustrated in FIG. IB,a mixture of an active agent and a binder 22 is combined with a solvent24. The resulting solution is then mixed 26, and poured into a castingmold 28. The solvent 24 is then allowed to evaporate 30. The resultingcasting can then be removed from the mold. As shown in FIG. IB, multipledevices 32 can be obtained from the mold.

In the above described methods, the concentration or quantity ofchymopapain per unit length of the rods can be determined from themanufacturing process. For example, the amount of active agent (e.g.,chymopapain) in an implant can be determined from the ratio of activeagent/binder in the mixture and from the volume or weight of theimplant. The appropriate length of rod can then be chosen to achieve thedesired dosage.

The implant as described above can be used for the treatment of patientswith a protruded disc and sciatica that meet the criteria for treatmentusing chemonucleolysis. Before implementing the method of treatment, thepatient can be worked up as if he or she would receive an injection ofchymopapain in solution.

A method of implanting a device as set forth above comprising achemonucleolysis agent such as chymopapain is illustrated in FIGS.2A-2H. For implantation of the device, a hypodermic needle orneedle/trocar assembly (shown) of appropriate size 42 (e.g., having aninner diameter slightly larger than 1 mm) can be used as shown in FIG.2A. As shown in FIG. 2B, the needle/trocar assembly can be inserted intothe disc space between adjacent vertebrae 34, 36 until the needle tippasses through the outer and inner annulus fibrosis 38 to the center(i.e., the nucleus pulposus) of the intervertebral disc. Needle tiplocation can be verified using fluoroscopy. If a needle/trocar assemblyis used, the needle 44 can then be removed leaving the hollow trocar 48in position as shown in FIG. 2C. As shown in FIGS. 2D-2G, an appropriatelength or lengths of implant 52 can then be inserted into the trocar anda stylet 50 can be used to push the length or lengths of rod 52 forwarduntil it is deposited near the center of the nuclear disc space.Although a stylet is shown, a blunt needle or other pushing device canbe employed. The trocar 48 and stylet 50 can then be removed and theimplant(s) left behind within the nucleus pulposus as shown in FIG. 2H.

In FIG. 2, three implants 52 are shown being implanted. However, more orfewer implants can be used to achieve the desired effect. Theperformance of a device comprising a chemonucleolysis agent such aschymopapain after implantation in a disc is illustrated in FIGS. 3A-3E.As shown in FIG. 3A, disc implants 52 (three shown) have been implantedinto the nucleus pulposus 40 of an intervertebral disc. Once implanted,the hygroscopic polymer in the device can absorb water rapidly in thehydrated nucleus pulposus. As a result, the implant can swell up andrelease the chemonucleolysis agent 54, 56 58 to the surrounding disctissues as shown in FIGS. 3B, 3C and 3D. The chymopapain released fromthe implant exerts a proteolytic action on the surrounding disc tissues.The implanted devices 52 are gradually eroded as shown in FIG. 3E andeventually disappear upon resorption.

The techniques and devices described herein provide a safe and effectivemeans for various types of disc treatment including, but not limited to,chemonucleolysis, pain-management, repair, and regeneration. Thesetechniques and devices also allow for the controlled and/or sustainedrelease of desirable active agents within the disc. Further, thetechniques and devices described herein can deliver an active agent to alocalized area of the disc. For example, an implant comprising achemonucleolysis agent such as chymopapain can be used to achievelocalized degradation of the nucleus of an intervertebral disc withoutthe destruction of other disc tissues including the annulus fibrosus. Inthis manner, reductions in the intradiscal pressure can be achievedusing an implant comprising a chemonucleolysis agent. The aforementionedtechniques and devices can also be used to avoid the potential sideeffects associated with the direct injection of a solution of an activeagent including leakage or overdose. Therefore, the techniques anddevices described herein can result in prolonged therapeutic effectswhile minimizing these and other adverse/side effects.

As set forth above, the devices can incorporate substances forchemonucleolysis such as chymopapain. The devices can also comprisepharmaceutical agents for therapeutic treatment. Exemplarypharmaceutical agents include, but are not limited to, steroids and painmedications. The device can also include growth factors and/or cells fordisc repair or regeneration. Since many of these materials are currentlyin use, the risks of using a device comprising these active agents arereduced.

The implants described herein also provide for minimally invasivedelivery or implantation. Moreover, the implants can be used to deliveran active agent to an essentially intact intervertebral discs. Forexample, by using the disclosed techniques, the surgical removal of disctissues is not required. Additionally, the disclosed methods and devicescan be used to treat various conditions of the disc (e.g. protrusion,herniation, discogenic pain, dehydration, degeneration, etc.) usingappropriate active agents while minimizing the potential detrimentalside effects typically associated with direct injection of active agentssuch as leakage or overdose.

Various means of incorporating active agents into a compact implantabledevice are provided. Methods for the delivery of the device into thenucleus of an intervertebral disc through a small annular opening arealso provided. Once implanted, the devices allow for the controlledand/or sustained release of active agents the disc tissues surroundingthe device.

According to a first embodiment, the device comprises at least two (2)materials: 1) an active agent (e.g., a therapeutic agent) and 2) abinder or matrix material. The binder is preferably an inert material.The device can be of any size and shape. The device is preferablycompact in cross-section for delivery into the disc space though a smallannular opening in the disc annulus.

The proposed methods and devices offer various advantages and can beused for various treatments of the ivt disc including, but not limitedto, chemonucleolysis, pain-management, disc repair, and discregeneration.

Set forth below are descriptions of various embodiments of devicescomprising a single active agent and methods of using these devices totreat an intervertebral disc.

Embodiment 1: According to this embodiment, chymopapain in powder formis mixed with a hygroscopic bioresorbable polymer in appropriate ratio.The mixture is consolidated under pressure and/or heat into elongatedrods with a diameter of approximately 1 mm. This device can be used forthe treatment of patients with a protruded disc and/or sciatica thatmeet the criteria for chemonucleolysis. The patient can be worked up asif he or she would receive an injection of chymopapain solution. Forimplantation, a hypodermic needle of an appropriate size (e.g., havingan inner diameter slightly larger than the device outer diameter) can beinserted into the disc space until the needle tip passes through theouter and inner annulus fibrosis to the center of the disc. The needletip location can be verified using fluoroscopy. An appropriate length ofimplant is then inserted into the needle and a stylet is used to pushthe rod forward until it is deposited near the center of the nucleardisc space. The needle is then removed and the implant is left behindwithin the nucleus pulposus. As the hygroscopic polymer absorbs waterrapidly in a hydrated nucleus pulposus, the rod swells up and releaseschymopapain to surrounding disc tissues for proteolytic action. Thedevice is gradually eroded and eventually disappears upon resorption.

Embodiment 2: According to this embodiment, pain medication in powderform is mixed with a bioresorbable polymer in an appropriate ratio. Themixture is consolidated under pressure and/or heat into elongated rodswith a diameter of approximately 1 mm. This device is proposed fortreatment of patients with discogentic pain.

For treatment, the patient can be worked up as if he or she wouldreceive an injection of pain medication in liquid form. A hypodermicneedle with appropriate size (e.g., an inner diameter slightly largerthan the outer diameter of the implant) is inserted into the disc spaceuntil the needle tip passes through the outer and inner annulus fibrosisto the center. Needle tip location can be verified using fluoroscopy. Anappropriate length or lengths of implant is then inserted into theneedle and a stylet or other pushing device is used to push the implantforward until it is deposited near the center of the nuclear disc space.The needle is then removed and the implant is left behind within thenucleus pulposus. As the polymer and pain medication absorb water, therod gradually releases pain medication to surrounding disc tissues forpain relief. The polymer gradually degrades and eventually disappearsupon resorption, which occurs after the medication is depleted.

Embodiment 3: According to this embodiment, growth factors in powderform are mixed with a natural bioresorbable polymer in an appropriateratio. The mixture is then consolidated under pressure into elongatedrods with a diameter of approximately 1 mm. Other techniques forincorporating active agents such as growth factors in powder form intoan inert binder are well known in the drug delivery industry and can beused to manufacture the implants. The concentration or quantity ofgrowth factors per unit length of the rods can be determined from theactive agent/binder ratio used in manufacturing the implant and from thedimensions of the implant.

This embodiment of the device is proposed for treatment of patients witha mild to moderately degenerated disc (i.e., a black disc). Forimplantation, a hypodermic needle with appropriate size (e.g., an innerdiameter slightly larger than the outer diameter of the implant) isinserted into the disc space until the needle tip passes through theouter and inner annulus fibrosis to the nucleus pulposus. Needle tiplocation can be verified using fluoroscopy. An appropriate length ofimplant is then inserted into the needle and a stylet or other pushingdevice (e.g., a blunt needle) is used to push the implant forward untilit is deposited near the center of the nuclear disc space. The needle isthen removed and the implant is left behind within the nucleus pulposus.As the polymer and growth factors in the implant absorbs water, the rodswells up, begins erosion and gradually releases growth factors tosurrounding disc tissues for disc repair or regeneration.

Embodiment 4: This embodiment involves the use of microspherescomprising an active agent. According to this embodiment, chymopapain isincorporated into microspheres comprising a binder (e.g., a hygroscopicbioresorbable polymer) at a desired ratio using methods known in thedrug delivery industry. The concentration or quantity of chymopapain perunit weight of microsphere can be determined from the ratio of activeagent to binder. This device is proposed for the treatment of patientswith a herniated disc and sciatica that meet the criteria for treatmentwith chemonucleolysis.

A method of using the above described device is illustrated in FIGS.9A-9D. For treatment, the patient can be worked up as if he or she wouldreceive an injection of chymopapain in solution. The microspheres 86 canbe mixed with a solvent 88 such as saline (FIG. 9A) and placed in adelivery device 90 (FIG. 9B). A syringe connected to a hypodermic needleof appropriate diameter is shown. The needle of the delivery device 90can then be inserted into the disc space until the needle tip is locatednear the center of the nucleus pulposus 40 (FIG. 9C). Needle tiplocation can be verified using fluoroscopy. An appropriate quantity ofmicrospheres 86 dispersed in solvent 88 can then be injected into thecenter of the disc (FIG. 9D). The needle is then removed (not shown) andthe microspheres are left behind within the nucleus pulposus 40. As thepolymer binder and chymopapain absorb water in the nucleus pulposus 40,the microspheres swell up, begin erosion and gradually releasechymopapain to surrounding disc tissues for proteolytic action.

Embodiment 5: This embodiment is similar to Embodiment 2 except that themicrospheres described in Embodiment 4 are used as an implant.

Embodiment 6: This embodiment is similar to Embodiment 3 except that themicrospheres described in Embodiment 4 are used as an implant.

Embodiments 7-9: These embodiments are similar to Embodiments 1-3 exceptthat implants comprising non-resorbable hydrogel polymer binders insteadof resorbable polymer binders are used.

Embodiments 10-12: These embodiments are similar to Embodiments 1-3except that implants comprising non-resorbable non-hydrogel polymerbinders instead of resorbable polymer binders are used. According tofurther embodiments of the invention, methods and devices for thetreatment multiple conditions of the disc (e.g. protrusion, herniation,discogenic pain, dehydration, degeneration, etc.) either simultaneouslyor sequentially are provided. These devices and methods can also be usedto minimize the potential side effects typically associated with thedirect injection of active agents in solution form to the intervertebraldisc such as leakage, overdose, or drug interactions.

Various methods of incorporating more than one active agent (e.g., achemonucleolysis agent, a pain medication, and/or a growth factor) intoa compact implantable device are provided. Also provided are methods forthe delivery of the device into the nucleus disc space through a smallannular opening. Once implanted, the device can exhibit controlledand/or sustained release of multiple active agents at different ratesand/or time points from the device to the surrounding disc tissues.

According to a further embodiment, when a growth factor is included inthe device, various types of cells can be injected into the disc spaceduring the growth factor releasing phase of the device in order topromote disc repair and regeneration.

As set forth above, the devices can comprise at least two differentactive agents (e.g., therapeutic substances) and one or more differentbinders or matrix materials. The device can be of any size and shape,but is preferably compact in cross-section for delivery to the discspace though a small annular opening.

The proposed methods and devices offer several advantages and can beapplied for multiple treatments of the disc either simultaneously orsequentially (e.g. chemonucleolysis, pain-management, repair,regeneration, etc.)

The devices and methods described herein provide a safe and effectivemeans for multiple types of disc treatment (e.g. chemonucleolysis,pain-management, repair, regeneration, etc.). The devices and methodscan also provide for the controlled and/or sustained release of multipleactive agents within the disc with a single implantation.

By using the techniques described herein, potential detrimental sideeffects associated with the injection of an active agent in solution canbe avoided. These side effects include leakage, overdose and/or druginteractions. The devices and techniques described herein also allow formultiple therapeutic effects to be achieved either simultaneously orsequentially with one implantation while minimizing adverse/sideeffects.

The devices can incorporate any combination of two or more activeagents. For example, the device can incorporate a combination of achemonucleolysis agent (e.g., chymopapain or chondroitinase ABC), apharmaceutical agent for therapeutic treatment (e.g., steroids and painmedication), a growth factor, and/or cells for disc repair orregeneration.

The risks involved in using the disclosed devices are reduced sincesimilar active agents have been used in existing therapies. In addition,the devices and methods provide for minimally invasive delivery orimplantation which can reduce discomfort to the patient duringimplantation and speed recovery.

Devices for the delivery of multiple active agents to an essentiallyintact intervertebral disc and methods of treatment using these devicesare described herein. These methods of treatment do not require thesurgical removal of disc tissue.

As set forth above, the devices can be used to treat multiple conditionsof the disc simultaneously or sequentially. Exemplary conditions whichcan be treated include, but are not limited to, protrusion, herniation,discogenic pain, dehydration, and degeneration. The use of the devicesfor treatment can minimize the potential side effects typicallyassociated with the direct injection of active agents in solution formsuch as leakage, overdose, or adverse drug interactions.

Various means of incorporating more than one active agent into a compactimplantable device are provided. In addition, methods for the deliveryof the device into the nucleus pulposus through a small annular openingare also provided. One implanted, the device can exhibit controlledand/or sustained release of active agents at different rates and/or timepoints from the device to surrounding disc tissues.

The device can comprise at least two different active agents (e.g.,therapeutic substances) and one or more inert binders (matrixmaterials). For example, each of the active agents can be combined witha different binder to achieve a desired release profile for each activeagent.

The device can be of any size and shape which can be implanted into anintervertebral disc. According to a preferred embodiment, the device iscompact in cross-section for delivery to the disc space though a smallannular opening in the annulus fibrosus of the disc.

The proposed methods and devices offer several advantages. Inparticular, the devices can be used to achieve multiple treatments ofthe disc simultaneously or sequentially (e.g. chemonucleolysis,pain-management, repair, regeneration, etc.).

Set forth below are various embodiments of devices comprising multipleactive agents and methods of using these devices to treat anintervertebral disc.

Embodiment 13: This device, which is depicted in FIG. 4, has an elongatesolid body with a circular cross section. The device 60 includes a core62 and a sheath 61. According to one embodiment, the core 62 comprisesone or more growth factor and the sheath 61 comprises a chemonucleolysisagent (e.g., chymopapain).

The shell can also comprise a binder. For example, the binder can be ahighly resorbable polymer which releases chymopapain quickly afterimplantation in the disc nucleus and therefore disappears within a shorttime (e.g. a few weeks) to expose the core 62 of the device. This phaseof release is denoted release phase 1. In release phase 1,chemonucleolysis is accomplished with the quick release of thechemonucleolysis agent. The core can comprise a more slowly resorbablepolymer. Once the core is exposed, the growth factors in the core can bereleased to stimulate disc cells to repair and/or regenerate the disc.This phase of release is denoted release phase 2. During release phase2, various cells may be optionally injected into the disc space toaccelerate the repair or regeneration process.

This device can be made using the following procedure. One or moregrowth factors are mixed with a first binder (e.g., a firstbioresorbable polymer) and consolidated into a small diameter rod underpressure and/or heat. The resulting rod is subsequently coated with amixture of a chemonucleolysis agent (e.g., chvmopapain) and a secondbioresorbable polymer.

This device can be used for treatment of patients with a protruded discand sciatica that meet the criteria for chemonucleolysis. Implantationcan be performed similarly to the method described above and illustratedin FIGS. 2A-2H. For example, the patient can be worked up as if he orshe would receive an injection of chymopapain in solution. Forimplantation, a hypodermic needle or a trocar/needle assembly withappropriate size (e.g., an inner diameter slightly larger than 1 mm) isinserted into the disc space until the needle tip passes through theouter and Inner annulus fibrosis to the center. Needle tip location canbe verified using fluoroscopy. An appropriate length of implant isinserted into the trocar and a blunt stylet or other pushing device isused to push the rod forward until it is deposited near the center ofthe nuclear disc space. The trocar is then removed and the implant isleft behind within the nucleus pulposus.

The performance of a device as set forth above after implantation intoan intervertebral disc is illustrated in FIGS. 5A-5E. In FIG. 5A, across-sectional representation of two adjacent vertebrae 34, 36 and anintervertebral disc comprising an annulus fibrosus 38 and a nucleuspulposus 40 is shown. In FIG. 5B, a device 60 is shown implanted in thenucleus pulposus 40.

As set forth above, the device 60 is an elongate solid body comprisingan inner core surrounded by a sheath. The core comprises growth factorsand a first bioresorbable polymer and the sheath comprises chymopapainand a second bioresorbable polymer wherein the first polymer is absorbedat a slower rate than the second polymer. Since the faster resorbablepolymer in the sheath absorbs water rapidly in the hydrated nucleuspulposus, the sheath swells up and releases chvmopapain to thesurrounding disc tissues for proteolysis and rapidly erodes away(release phase I of 2).

Release phase I of the device is illustrated in FIGS. 5B and 5C. Asshown in FIGS. 5B and 5C, the release 63 of the chemonucleolysis agentresults in controlled degradation of the disc nucleus 64. Thechemonucleolysis which occurs during release phase 1 can result in thereduction of intradiscal pressure and disc dehydration which canalleviate pain and sciatica.

As the sheath of the device is degraded, the core is exposed. The coreof the device subsequently degrades and releases one or more growthfactors 66, 68 to begin the disc repair/regeneration process (releasephase 2 of 2). Release phase 2 is illustrated in FIGS. 5D and 5E. Asshown in FIGS. 5D and 5E, the release of the growth factors 66, 68 intothe nucleus during phase 2 can stimulate disc cells to repair orregenerate the disc 65 by synthesis of proteoglycan. This can helpprevent, reduce or slow disc degeneration that may result fromnucleolysis after treatment with a chemonucleolysis agent such aschymopapain. The core of the device is gradually eroded as shown in FIG.5E and the device eventually disappears upon resorption.

Embodiment 14: In this embodiment, the device described above inEmbodiment 13 is implanted into the nucleus of a disc and notochordalcells are injected into the disc space during phase 2 of the release(i.e. during release of growth factors from the core of the deviceduring the disc repair/regeneration phase). This process is illustratedin FIG. 6. In particular, as shown in FIG. 6D, cells 72 loaded in asyringe 70 can be injected into the nucleus during the release of theone or more growth factors 66. The cells can be injected after thecompletion of chymonucleolysis and/or during the release of the growthfactor 66 for disc repair/regeneration. Depending on the device, thismay up to a few weeks to a few months after implantation.

Embodiment 15: This embodiment is similar to Embodiment 14 exceptfibrochondrocyte (instead of notochordal) cells are injected into thedisc space during release phase 2.

Embodiment 16: This embodiment is similar to Embodiment 15 exceptmesenchymal stem cells (instead of notochordal cells) are injected intothe disc space during release phase 2.

Embodiment 17: This embodiment is similar to Embodiment 13 except painmedication is used as an active agent in the core of the device insteadof growth factors. Implantation of this embodiment of the device allowsfor pain management following chemonucleolysis of the nucleus.

Embodiment 18: This embodiment is similar to Embodiment 13 except thatboth a pain medication and chymopapain are incorporated into the sheathof the device for simultaneous pain relief and chemonucleolysis duringthe first phase of release. One or more growth factors are incorporatedinto the core of the device.

Embodiment 19: This embodiment is similar to Embodiment 13 except thatthe device comprises three regions instead of two: a core, an innersheath, and an outer sheath. According to one embodiment, painmedication can be incorporated into the outer sheath and achemonucleolysis agent (e.g., chymopapain) can be incorporated into theinner sheath of the device. Growth factors can be incorporated into thecore of the device.

A device of his type is shown in FIG. 7. As shown in FIG. 7, the device74 comprises a core 80, an inner sheath 78 and an outer sheath 76. Thisdevice has three release phases. During phase I of release, the activeagent (e.g., a pain medication) is first released from the outer sheath.During phase 2, a chemonucleolysis agent (e.g., chymopapain) is releasedfrom the inner sheath for chemonucleolysis. During phase 3, one or moregrowth factors are released from the core for disc repair andregeneration.

Embodiment 20: This embodiment is similar to Embodiment 14 except theimplanted devices are microspheres instead of elongate solid bodies. Themicrospheres can be suspended in solution (e.g., saline) and injectedinto the intervertebral disc space using a hypodermic needle.

A microsphere comprising first and second active agents is shown in FIG.8. As shown in FIG. 8, the microsphere 81 includes a core 82 comprisinga first active agent and a shell 84 comprising a second active agent.According to an exemplary embodiment, the first active agent can be agrowth factor and the second active agent can be a chemonucleolysisagent such as chymopapain.

Embodiment 21: This embodiment is similar to Embodiment 13 except thatthe sheath of the device comprises chymopapain and atemperature-sensitive bioresorbable hydrogel. As soon as the hydrogelcomes into contact with body fluid at 37° C. within the disc nucleus, itundergoes a phase transformation to allow the release of chymopapain ata high rate for rapid chemonucleolysis.

Embodiment 22: This embodiment is similar to Embodiment 14 except thatthe core of the device that contains one or more growth factorscomprises a pH-sensitive resorbable polymer binder. Afterchemonucleolysis, the polymer binder in the sheath degradessignificantly and lowers the local pH. This change in pH triggers thecore to release the one or more growth factors for disc repair and/orregeneration.

Embodiment 23: This embodiment is similar to Embodiment 14 exceptchondroitinase ABC is used instead of chymopapain as a chemonucleolysisagent.

Embodiment 24: This embodiment relates to the treatment of a “black”disc. In the case of a degenerated, dehydrated or “black” disc,chemonucleolysis is not necessary. A device suitable for the treatmentof such a disc is provided which is similar to Embodiment 14 except thatpain medication is used as an active agent in the sheath instead ofchymopapain. Growth factors are included in the core for repair orregeneration of the disc. In an alternative embodiment, microspherescomprising pain medication in the shell and growth factors in the corecan also be used. The microspheres can be implanted into anintervertebral disc using the technique illustrated in FIG. 9.

Various alternative embodiments of devices comprising first and secondactive agents are shown in FIGS. 10-15. FIG. 10 illustrates analternative embodiment of an intervertebral disc implant for thedelivery of multiple (i.e., two) active agents. As shown in FIG. 10, thedevice 98 is an elongate solid body comprising a first region 100 and asecond region 102 adjacent to the first region 100. The first region 100can comprise a first active agent and the second region 102 can comprisea second active agent. Each of the regions 100, 102 can also comprise abinder. The binder in each of the regions can be the same or different.The binder in each region can be chosen to achieve the desired releasecharacteristics for each active agent.

FIG. 11 illustrates an alternative embodiment of an intervertebral discimplant for the delivery of multiple (i.e., three) active agents. Asshown in FIG. 11, the device 104 is an elongate solid body comprising afirst region 106, a second region 108 adjacent to the first region 106,and a third region 110 adjacent to the second region 108. The firstregion 106 can comprise a first active agent, the second region 108 cancomprise a second active agent different than the first active agent,and the third region 110 can comprise a third active agent differentthan the first and second active agents. Each of the regions 106, 108,110 can also comprise a binder. The binder in each of the regions 106,108, 110 can be the same or different. The binder in each region 106,108, 110 can be chosen to achieve the desired release characteristicsfor the active agent contained in that region.

FIG. 12 illustrates an alternative embodiment of an intervertebral discimplant for the delivery of multiple (i.e., three) active agents. Asshown in FIG. 12, the device 112 has a sheath/core configuration. Thesheath comprises a first region 114 and a second region 116 each ofwhich can comprise a different active agent. A third active agent isincluded in the core 118. Each of the regions 114, 116, 118 can alsocomprise a binder. The binder in each of the regions 114, 116, 118 canbe the same or different. The binder in each region 114, 116, 118 can bechosen to achieve the desired release characteristics for each activeagent.

FIG. 13 illustrates an alternative embodiment of an intervertebral discimplant for the delivery of multiple (i.e., three) active agents. Asshown in FIG. 13, the device 120 has a sheath/core configuration. Thesheath 126 can comprise a first active agent. The core comprises a firstregion 122 and a second region 124 each of which can comprise adifferent active agent (e.g., second and third active agents,respectively). Each of the regions 122, 124, 126 can also comprise abinder. The binder in each of the regions 122, 124, 126 can be the sameor different. The binder in each region 122, 124, 126 can be chosen toachieve the desired release characteristics for each active agent.

FIG. 14 illustrates an alternative embodiment of an intervertebral discimplant for the delivery of multiple (i.e., two) active agents having anelongate configuration. As shown in FIG. 14, the device 128 comprisesregions of a first active agent 130 alternating with regions of a secondactive agent 132. Each of the regions can also comprise a binder. Thebinder in each of regions 130 and regions 132 can be the same ordifferent. The binder in each of regions 130 and regions 132 can bechosen to achieve the desired release characteristics for each activeagent.

FIG. 15 illustrates an alternative embodiment of an intervertebral discimplant for the delivery of multiple active agents having an elongateconfiguration. As shown in FIG. 15, the device 134 comprises adjacentregions 136, 138, 140, 142, 144, 146, 148 each comprising a differentactive agent. Although seven regions are shown, devices having more orfewer regions can also be used. Each of the regions 136, 138, 140, 142,144, 146, 148 can also comprise a binder. The binder in each of theregions 136, 138, 140, 142, 144, 146, 148 can be the same or different.The binder in each of the regions 136, 138, 140, 142, 144, 146, 148 canbe chosen to achieve the desired release characteristics for each activeagent.

The devices can have be of any shape and size suitable for implantationinto the intervertebral space of a mammal. For example, the device canbe an elongate solid body. According to one embodiment, the crosssection of the elongate solid body can have a maximum dimension of five(5) mm or less. According to further embodiments, the cross section ofthe elongate solid body can have a maximum dimension of three (3) mm orless, two (2) mm or less, or one (1) mm or less. The phrase “maximumdimension” refers to the longest straight line that can be drawn on agiven area. For example, the maximum dimension of a circle is itsdiameter. The cross-section of the device can be of any shape. Forexample, the cross section can be circular or polygonal (e.g.,octagonal).

The shape and size of the implant can be chosen to achieve the desiredrelease characteristics from the device. FIGS. 16A-16O illustratevarious profile shapes for elongate solid body intervertebral discimplants. The insertion end of the device can be square (not shown).Alternatively, as shown in FIGS. 16B and 16D, the elongate solid body ofthe device 156, 164 can have a rounded insertion end 158, 166.Alternatively, as shown in FIGS. 16A, 16C and 16E-O the elongate solidbody of the device 152, 160, 168, 174, 180, 186, 192, 198, 204, 210,216, 222, 226 can have a tapered or pointed insertion end 154, 162, 170,176, 182, 188, 194, 200, 206, 212, 218, 223, 227 The shape of theleading end can be chosen to facilitate implantation. For example, atapered or rounded leading end can require less force to insert througha small aperture than a square leading end.

As shown in FIGS. 16A-16D, the end opposite the insertion end (i.e., thetrailing end) of the elongate solid body of the device 152, 156, 160,164 may be square. Alternatively, the trailing end of the elongate solidbody may be rounded 172 or tapered 174 as shown in FIGS. 16E and 16F,respectively, or concave 184, 190, 196, 202, 208 as shown in FIGS.16G-16K.

FIGS. 16L-16O are profile shapes of alternative elongate solid bodyimplants. As shown in FIG. 16L, the implant 210 can have a tapered end212 and a series of serrations 214 along its length. Alternatively, asshown in FIG. 16M, the implant 216 can have a tapered end 218 and aseries of grooves 220 running down its length. As shown in FIG. 16N, animplant 222 having a tapered end 223 and a series of angled indentations224 along its length is also provided. As shown in FIG. 16O, an implant226 having a tapered end 222 and threads 228 running the length of theremainder of the solid body is also provided.

FIG. 17 illustrates an alternative embodiment of an intervertebral discimplant 230 for the delivery of multiple (i.e., two) active agents. Asshown in FIG. 17, the device 230 has an elongate configurationcomprising two regions 232, 234 each of which contain a different activeagent and a tapered insertion end 231. The device also has a coating 236to provide lubricity. The coating 236 may be a hydrogel coating.

FIG. 18 illustrates an alternative embodiment of an intervertebral discimplant for the delivery of multiple (i.e., two) active agents. As shownin FIG. 18, the device 238 has an elongate configuration, a pointedinsertion end 239, and a coating 236 to provide lubricity. The devicealso comprises x-ray markers 240 (two shown). As shown in FIG. 18, thex-ray markers 240 are beads. As also shown in FIG. 18, each of theregions of the device 232, 234 comprises a marker 240. The x-ray markers240 can comprise a material detectable by x-ray. Exemplary materials forthe x-ray markers 240 include, but are not limited to, barium sulfate,platinum and tantalum.

FIG. 19 illustrates an alternative embodiment of an intervertebral discimplant for the delivery, of multiple (i.e., two) active agents. Asshown in FIG. 19, the device 242 has an elongate configuration, apointed insertion end 243, and a coating 236 to provide lubricity. Thedevice also has an x-ray marker 244 in the form of a thread. The x-raymarker 244 can comprise a material detectable by x-ray. Exemplarymaterials for the x-ray marker 244 include, but are not limited to,barium sulfate, platinum and tantalum.

FIGS. 20A and 20B illustrate a method of implanting an intervertebraldisc implant of the type shown in FIGS. 16A-16O. As shown in FIG. 20A,an aperture 248 is made through the annulus 38 and into the nucleus 40of an intervertebral disc. A hollow tube 250 (e.g., a trocar) having aninternal diameter slightly larger than the outer diameter of the device246 being implanted is then placed into contact with the annulus 38 suchthat the end of the tube 250 is over the aperture 248. The implant 246is placed in the tube and pushed through the aperture and into thenucleus 40 as shown in FIG. 20B. Insertion of the device 246 can beaccomplished using a pushing device 252 such as a blunted needle or astylet or a puch rod.

The implant shown in FIGS. 20A and 20B has a concave trailing end 253.The concave trailing end 253 helps to keep the pushing device engaged inthe implant 246 as the implant 246 is being inserted into the nucleus40.

As shown in FIG. 20B, during insertion, the tissues surrounding theaperture 248 collapse behind the inserted device 246 thereby partiallyclosing the dilated aperture 248. After insertion, the pushing device252 is removed (not shown) thereby leaving behind an aperture in theannulus that is significantly smaller than the diameter of the deviceinserted. Insertion of a device larger than the aperture is possible dueto the viscoelastic nature of the annular tissue and the very shorttimes involved in the dilation/insertion step.

Exemplary active agents which can be incorporated into the devicesinclude, but are not limited to:

chemonucleolysis agents such as chymopapain, collagenase,chondroitinase-ABC and human proteolytic enzymes;

pain medications such as codeine, propoxyphene, hydrocodone, andoxycodone; and

growth factors such as transforming growth factor β proteins, bonemorphogenetic proteins, fibroblast growth factors, platelet-derivedgrowth factors, and insulin-like growth factors.

Any of the aforementioned active agents or combinations thereof can beincorporated into the device.

Examples of binders or matrix materials include, but are not limited to:

non-resorbable polymers such as poly(urethanes), poly(siloxanes),poly(methyl methacrylate), poly(ethylene), poly(vinyl alcohol,poly(vinyl pyrrolidon), poly(2-hydroxy ethyl methacrylate), poly(acrylicacid), poly(ethylene-co-vinyl acetate, poly(ethylene glycol),poly(methacrylic acid), and polyacrylamide;

bioresorbable polymers such as polylactides (PLA), polyglycolides (PGA),poly(lactide-co-glycolides) (PLGA), polyanhydrides, and polyorthoesters;and

natural polymers such as: polysaccharides, collagens, silk, elastin,keratin, albumin, and fibrin.

Any combination of the above binders can be used in the device.

When a growth factor is included in the device, various types of cellscan be injected into the disc space during the growth factor releasingphase of the device in order to promote disc repair and regeneration.Exemplary cells that can be injected into the intervertebral disc duringthe growth-factor-releasing phase of the device include, but are notlimited to, notochords, fibrochrondrocytes, and mesenchymal stem cells.The cells can be modified with a growth factor. For example, the cellscan be transfected with a nucleic acid (e.g., an expression vector)encoding a growth factor such as a bone morphogenetic protein or a LIMmineralization protein.

As set forth above, the intervertebral disc implant can be formed byconsolidating an admixture comprising a binder and one or more activeagents into a solid body. Alternatively, the intervertebral disc implantcan include a plurality of particles at least some of which comprise anactive agent wherein the particles are unconsolidated (i.e., in looseadmixture). The implant comprising particulate material can be implantedinto an intervertebral disc using a hollow tube (e.g., a trocar) as adelivery device. The implant can further include particles comprising abinder. The particles comprising a binder can be mixed with theparticles comprising the active agent to facilitate handling anddelivery of the particulate material into the disc nucleus.

According to a further embodiment, at least some of the individualparticles in the implant can comprise an active agent and a binder.Particles comprising an active agent and a binder can be made by mixingtogether particles of the active agent and the binder, forming aconsolidated solid body from the admixture (e.g., using heat and/orpressure), and comminuting the solid body to form particles of thedesired size.

An implant comprising a plurality of particles wherein at least some ofthe particles comprise a first active agent and at least some of theparticles comprise a second active agent is also provided. The implantaccording to this embodiment can further comprise a binder. The implantcan be made by mixing particles of the first and second active agentswith particles of the binder to form an implant. Alternatively, anadmixture of first and second active agents and binder can beconsolidated into a solid body and comminuted into particles to form theimplant. According to this embodiment, individual particles in theimplant comprise the first and second active agents as well as thebinder. Implants comprising additional active agents (i.e., three ormore) can also be made using the techniques described above.

For either the solid body (e.g., consolidated) implants or theparticulate (e.g., non-consolidated) implants, the particles comprisingactive agent(s) in the implant can be sized to achieve a desired releaseprofile. Smaller particles have a higher surface area and will thereforetypically result in more rapid release of the active agent. According toone embodiment, the particles of active agent(s) in the implant can havean average diameter of 0.1 to 500 μm. According to further exemplaryembodiments, the particles of active agent in the implant can have anaverage diameter of from 0.5 to 250 pm or from 1 to 100 μm. When theimplant is a solid body including multiple regions each comprising adifferent active agent, active agents having different particle sizescan be used in each region of the implant to achieve the desired releasecharacteristics for that active agent.

If a binder is used, the amount of binder in the implant can also bevaried to achieve the desired release characteristics for the activeagent(s) in the implant. In the case of particulate implants, the amountof binder can also be varied to achieve the desired handlingcharacteristics for the particulate material. According to a firstexemplary embodiment, the implant can comprise from 10 to 100% by volumeof the active agent with the remainder (i.e., 0 to 90% by volume) beingbinder. According to a further exemplary embodiment, the implant cancomprise from 25 to 75% by volume of the active agent with the remainder(i.e., 25 to 75 by volume) being binder. When the implant is a solidbody including multiple regions each comprising a different activeagent, different amounts of binder can be used in each region of theimplant to achieve the desired release characteristics for that activeagent.

EXPERIMENTAL

Below is a summary of an experiment involving the implantation of adevice comprising chymopapain as a chemonucleolysis agent and collagenas a binder.

Materials

Chymopapain powder

Fascian allogenic collagen

Saline

Methods

Three thoracic or lumbar pig discs were used in this experiment. Onedisc remained untreated as the control.

A second disc was injected with approximately 0.003 g of hymopapainpowder in 0.7 cc saline.

An implant according to an embodiment of the invention comprising anunconsolidated mixture of chymopapain powder and a binder was implantedinto a third disc. The implant included approximately 0.003 g ofchymopapain powder mixed with collagen powder (5:1 collagen/chymopapainapproximate volume ratio).

Each of the discs were left in a refrigerator for approximately 5 daysbefore sectioning for observation. Pictures of sections of each discwere then taken. FIG. 21A is a picture of the control disc. FIG. 21B isa picture of the second disc. FIG. 21C is a picture of the third disc.

Results and Discussion

As can be seen from FIG. 21B, the nucleus pulposus of the disc treatedwith chymopapain solution appeared as a viscous liquid plus gel mixturewhich was significantly more flowable compared to the gelatinousconsistency of the nucleus of the control disc (FIG. 21A). This isprobably due to the breakdown of the nucleus pulposus matrix as well asthe presence of the original injected liquid. In addition, leakage ofthe injected chymopapain solution was observed at the injection site ofthe annulus fibrosis. This is most likely a result of the highintradiscal pressure, which was exacerbated by the injected liquid.Clinical complications that are associated with injection of chymopapainin chemonucleolysis are probably attributed, in part, to this observedleakage.

As can be seen from FIG. 21C, The nucleus pulposus of the disc treatedwith the implant comprising chymopapain powder appeared to have the sameconsistency as that of the control disc (FIG. 21A) but with noticeablysmaller volume. Further, the inserted device had almost completelydisappeared.

The chymopapain powder also appeared to break down the added collagen.Although it was expected that, in powder form, chymopapain would workmore slowly in breaking down the nucleus pulposus, the presence ofsignificant quantities of added collagen may have interfered with theproteolytic action of chymopapain on the nucleus.

The above observations show that chymopapain in solution form worksrapidly in breaking down the nucleus pulposus while implantation of asolid device comprising chymopapain in solid form (e.g., in powder form)works more slowly. Without wishing to be bound by theory, it is believedthat the slower action of the solid implant results from diffusioncontrol of the chymopapain. The above observations also show that, byusing an implant comprising a chemonucleolysis agent in solid form,localized degradation of the disc nucleus can be achieved.

As a result of this study, it can be clearly seen that chymopapain insolid form, when delivered to the nucleus pulposus in the form of acontrolled release device, can help prevent or minimize complicationsassociated with the leakage of chymopapain resulting from directinjection of chymopapain in solution.

While the foregoing specification teaches the principles of the presentinvention, with examples provided for the purpose of illustration, itwill be appreciated by one skilled in the art from reading thisdisclosure that various changes in form and detail can be made withoutdeparting from the true scope of the invention.

1. An intervertebral disc implant comprising a chemonucleolysis agent insolid form, wherein the implant, when placed into the nucleus pulposusof an intervertebral disc, releases the chemonucleolysis agent into thenuclear disc tissue surrounding the implant to proteolytically degradethe tissue.
 2. The intervertebral disc implant of claim 1, wherein theimplant includes a plurality of particles and wherein at least some ofthe particles comprise the chemonucleolysis agent.
 3. The intervertebraldisc implant of claim 1, wherein the implant further comprises a binder.4. The intervertebral disc implant of claim 2, wherein the particlescomprising the chemonucleolysis agent have an average diameter of 0.1 to500 μm.
 5. The intervertebral disc implant of claim 2, wherein theparticles comprising the chemonucleolysis agent have an average diameterof 0.5 to 250 μm.
 6. The intervertebral disc implant of claim 2, whereinthe particles comprising the chemonucleolysis agent have an averagediameter of 1 to 100 μm.
 7. The intervertebral disc implant of claim 1,wherein the chemonucleolysis agent is selected from the group consistingof chymopapain, collagenase, chondroitinase-ABC and human proteolyticenzymes.
 8. The intervertebral disc implant of claim 1, wherein theimplant is a solid body.
 9. The intervertebral disc implant of claim 8,wherein the solid body is an elongate solid body.
 10. The intervertebraldisc implant of claim 8, wherein the solid body is an elongate solidbody having a tapered or rounded end.
 11. The intervertebral discimplant of claim 8, wherein the solid body is a microsphere.
 12. Theintervertebral disc implant of claim 8, wherein the solid body has aprofile shape selected from the group consisting of the profile shapesdepicted in FIGS. 16A, 16B, 16C, 16D, 16E, 16F, 16G, 16H, 161, 16J, 16K,16L, 16M, 16N and 16O.
 13. The intervertebral disc implant of claim 8,wherein the solid body has a circular cross section.
 14. Theintervertebral disc implant of claim 1, wherein the implant furthercomprises a binder.
 15. The intervertebral disc implant of claim 14,wherein the implant comprises up to 90% by volume of the binder.
 16. Theintervertebral disc implant of claim 14, wherein the implant comprisesfrom 25 to 75% by volume of the binder.
 17. The intervertebral discimplant of claim 14, wherein the binder is a polymer.
 18. Theintervertebral disc implant of claim 14, wherein the binder is anon-resorbable polymer, a bioresorbable polymer, or a naturallyoccurring polymer.
 19. The intervertebral disc implant of claim 14,wherein the binder is a non-resorbable polymer selected from the groupconsisting of polyurethanes, polysiloxanes, polymethyl methacrylate,polyethylene, polyvinyl alcohol, polyvinyl pyrrolidone, poly(2-hydroxyethyl methacrylate), polyacrylic acid, poly(ethylene-co-vinyl acetate),polyethylene glycol, polymethacrylic acid, and polyacrylamide.
 20. Theintervertebral disc implant of claim 14, wherein the binder is abioresorbable polymer selected from the group consisting ofpolylactides, polyglycolides, polylactide-co-glycolides, polyanhydrides,and polyorthoesters.
 21. The intervertebral disc implant of claim 14,wherein the binder is a naturally occurring polymer selected from thegroup consisting of polysaccharides, collagens, silk, elastin, keratin,albumin, and fibrin.
 22. The intervertebral disc implant of claim 1,wherein the implant further comprises a second active agent differentthan the chemonucleolysis agent.
 23. The intervertebral disc implant ofclaim 22, wherein the second active agent is a pain medication or agrowth factor.
 24. The intervertebral disc implant of claim 22, whereinthe second active agent is a pain medication selected from the groupconsisting of codeine, propoxyphene, hydrocodone, and oxycodone.
 25. Theintervertebral disc implant of claim 22, wherein the second active agentis a growth factor selected from the group consisting of a transforminggrowth factor-β protein, a bone morphogenetic protein, a fibroblastgrowth factor, a platelet-derived growth factor, and an insulin-likegrowth factor.
 26. The implant of claim 8, wherein the solid bodyfurther comprises a hydrogel coating.
 27. The implant of claim 8,further comprising an x-ray marker.
 28. The implant of claim 27, whereinthe x-ray marker is a bead or a thread.
 29. The implant of claim 27,wherein the x-ray marker comprises barium sulfate, platinum or tantalum.30. The implant of claim 9, wherein the elongate solid body has nocross-sectional area with a maximum dimension greater than 5 mm.
 31. Theimplant of claim 9, wherein the elongate solid body has nocross-sectional area with a maximum dimension greater than 3 mm.
 32. Theimplant of claim 9, wherein the elongate solid body has nocross-sectional area with a maximum dimension greater than 1 mm.